William Murphy (1960) - X-Ray Treatment of Chronic Leukemia

Distinguished guests, ladies and gentlemen. I must first apologise for not giving my address in German. I’m sure, however, that you will understand my Boston and perhaps Cambridge English much better than my German. (Applause) I sort of feel that you might feel just now very much as I did quite a number of years ago after listening to these 2 beautifully presented papers this morning with so much important information. Quite a number of years ago when I was taking my examinations to practice medicine in the state of Massachusetts, part of the examination was an oral one. Each physician spent several minutes discussing their own subject with a candidate: surgery, internal medicine, paediatrics and so on. So after having been in conference with the surgeon for some minutes and not feeling too happy about the outcome, I approached the next man who asked me what I intended to do. I said, “I thought I’d practice medicine.” He said, “Are you interested in obstetrics?” He smiled and said: “Well that happens to be my subject to examine you on.” And he said, “I rather judge you won’t be very much interested in my questions, so let’s just relax and talk a few minutes.” So I feel perhaps that what we should do now is just relax, rather than trying to struggle through a discussion of the treatment of leukaemia. The work that I want to present today was originally planned as a joint report with the late Doctor Merrill Sauceman, who was a Harvard Medical School professor of radiology at Peter Bent Brigham Hospital. The work deals with certain data concerning 107 patients with chronic leukaemia treated at the hospital by Roentgen irradiation for the most part in cooperation with Dr. Sauceman until his retirement in 1956. An attempt has been made to include in this group only those with chronic leukaemia, although it’s a well recognised fact that it’s not always possible to distinguish between the chronic and the acute or subacute varieties. May I have the first slide please. The diagnosis was ordinarily made on the basis of the clinical evaluation and the peripheral blood picture. This just shows a low-power photomicrograph of the picture in chronic lymphocytic leukaemia. If there were blast forms present in any considerable degree or number, the condition was considered to be acute rather than chronic. The next slide please. I’m sorry that these do not show up well. The next slide. This is a high-power of the lymphocytic and a low-power of granulocytic. And the next one shows a higher power of the granulocytic. The next slide please. You see an eosinophil in the far corner and a myelocyte in the centre. It is not my intention today to try to discuss the nature of the leukaemic process or the aetiology of the disease. Such a discussion would entail considerable speculation and perhaps theory and it would not help us to solve the problem of treatment, at least for the present. We do, however, now consider leukaemia as a malignant cancer and we know that there are certain irritants that do tend to precipitate the disease. That is irradiation; chemical, physical and viral irritations have been shown to produce the disease in some instances. During the earlier years, as was the prevailing custom, and occasionally later, treatment was directed either to the spleen, the chest, the long bones or masses of lymph nodes. Following the remission treatment was usually withheld until another relapse occurred and the general condition of the patient was poor. The rather large doses of x-rays required were frequently followed by anorexia, severe nausea and vomiting and general malaise. After recovery from this there was a short period with some degree of wellbeing, followed by the next relapse and then of course requiring another round of treatment. It was observed, however, that treatment over the long bones only was followed by a satisfactory response of the leukocytes but with less of the toxic effects so frequently observed following treatment of the spleen or chest. In view of these facts it was decided that the method of treatment would be modified in 2 major respects in the belief that some of the unpleasant effects of therapy could be avoided and also that we might perhaps actually increase the lifespan. The first modification was to apply treatment in small dosage over the entire trunk from the mid-thighs upward at 1 metre distance alternating front and back, so-called Teleoroentgen therapy. The second modification was to start treatment when the leukocyte levels tended to rise above 40,000 cells per mm^3 rather than waiting until a more severe relapse, thus maintaining a rather uniformly near normal leukocyte level. This we decided to refer to as spray technique as opposed to the local application previously used. Doses of from 15 to 50 or 60 Roentgens were used depending upon the patient’s condition and the effect anticipated. This method used was discussed in a paper in 1940. The spray technique was introduced in the early part of 1934 and with few exceptions has been used as the principle method of treatment since that time in our clinic. Local treatment to masses of lymph nodes or to the spleen was used when it was indicated. In order to compare the relative effects of the spray and local techniques, the patients treated by each method are considered separately according to the predominating technique used. A few of each group also received some form of chemical therapy at some time during the course of their illness. May I have the next slide please? The patients with granulocytic leukaemia were divided equally in respect to sex. In the lymphocytic group there were 27 male and 20 female. Now this slide shows the age at onset or the first definite signs or symptoms recognised as manifestations of the disease. The age differed somewhat in the 2 groups. In the lymphocytic group we find only 6 of the patients developing the disease before the 5th decade, whereas in the granulocytic group, to your right, over half of the patients developed the disease before the 5th decade. In other words the granulocytic leukaemia is a disease of younger people ordinarily, although again you see at the bottom in the 8th decade 1 patient in the lymphocytic group and 2 in the granulocytic. The youngest patient in the lymphocytic was 36 and in the granulocytic 23. And the oldest in each of the groups was 82 and 85 at the time of onset. May I have the next slide please? The results of treatment as indicated by length of survival after onset by the 2 techniques used are shown in these next 2 slides. The percentage of patients surviving 3 years... these represent the years of survival, 3 to 7. The survival percentage in the 2 groups was about the same in the groups treated by spray or by local in both series: However, at 4 years there’s some difference: Following through with the lymphocytic at 5 years 59% under spray treatment survive and only 27 under local treatment. The survival percentage was the same in both forms of treatment in the granulocytic group. And at 7 years 47% of the patients were still alive by the spray method and only 20 with the local treatment. The next slide please. This shows the classification according to years, the number of patients still living at those intervals. The average survival rate in the lymphocytic leukaemia patients treated by the spray method was 6.8 years and in those treated by the local method 4.6. In the granulocytic group the comparable figures are 3.1 and 2.8. Moffitt and Lawrence have cited 31 instances of leukaemia surviving at least 5 years. McGavran cited 1 instance of a patient surviving 25 years. Taking that into consideration we have here 5 patients surviving 10 years; 1 11, 12, 16, 17 and 26 years. That seems to be about the longest survival. In the granulocytic group 2 patients survived 9 years. The figures indicating survival time, as shown in these 2 slides, compare favourably with those recorded in previously reported series. They also suggest some advantage in duration of survival time for those treated by the spray method as opposed to the local technique although this advantage is not striking. There has, however, been a great difference between the effects of the 2 techniques in respect to the condition of the patients during their illness. Those treated in large dosage locally over the chest or spleen and at the time of severe relapse have, as I’ve previously noted, experienced periods of rather disturbing malaise, anorexia, nausea and vomiting after their treatment with only brief periods of wellbeing between time. Whereas those treated with the small dosage by spray technique have suffered few ill effects as the result of treatment and have in general lived normal lives carrying on their usual occupations throughout their periods of illness. The mild anorexia or nausea which occurred in the occasional patient was readily controlled by intramuscular injections of 50 to 100 mg of pyridoxine hydrochloride. Those who experienced nausea or anorexia on the first exposure were after that treated 1 hour or 2 with pyridoxine before the next x-ray treatment was given. It may be profitable to record briefly the regimen recommended for the management of treatment in the patient after the diagnosis has been established. This will of course vary depending on many circumstances. If the leukocyte level is high, the patient with all pertinent data regarding history and blood picture is referred to the radiologist for treatment. Spray treatment may be applied daily, or on alternate days, and must be controlled by leukocyte counts before each exposure. Pyridoxine should be injected before each treatment if indicated. Treatment is continued in small dosage until the leukocyte level has dropped to 30,000 or perhaps lower, depending upon the rate of the drop. As one may expect the count to continue to drop for several days after treatment is stopped, it is desirable to check the count in about a week as a guide to subsequent courses of treatment. The patient should be seen and the count checked thereafter every 4 to 6 weeks. When there is again a tendency for the leukocytes to increase, In this way an attempt is made to maintain fairly uniform and near normal leukocyte levels. This method of treatment, always carried out in consultation between the physician and radiologist, is used for control of the leukocytes, though massive enlargement of lymph nodes may require local therapy for their control. It’s rarely necessary to treat the spleen locally even though it’s slightly enlarged, for if one uses spray treatment regularly, the size of the spleen usually subsides also. If the leukocyte level is not high when the diagnosis is made, treatment should be delayed until such time as the patient either shows definite indications of a relapse approaching, or, preferably, as the leukocyte count rises to above 40,000. May I have the next slide? This patient was followed for 5 years before treatment was started. This shows the 5-year period. Although his leukocyte count was tending to rise, treatment was not started for he was asymptomatic. He did have arthritis. Note that this was before the days of cortisone but that was not very troublesome. The next slide shows the course of events during treatment which he was still living at the end of 5 years. And in all lived 7 years during the course of treatment during which time, as you will see, the leukocyte levels were maintained low and his general physical health was excellent. He worked regularly and subsequently died, at a time when the leukaemia was well controlled, of a coronary heart attack. This patient lived in all 12 years during the time that his disease was recognised. May I have the next slide? If the lymph node enlargement is the presenting problem such as in this patient, local application rather than spray will be indicated. This is illustrated by this patient whose complaint was of deafness. His aurist thought this might be due to pressure from enlarged lymph nodes, which proved to be the case for when the lymph nodes were treated his deafness totally disappeared. May I have the next slide? And subsequently he was followed with spray treatment but, unfortunately, circumstances were such that he died 2 years later. Death was not related to the leukaemia, however, but he had a haemorrhage, a gastric haemorrhage, one very stormy, snowy night on his farm in Canada which was 20 miles from the nearest medical attention. His history suggested that the haemorrhage was from a peptic ulcer. He had been up to that time in excellent condition so far as the leukaemia was concerned. And although he was then 72 years of age I suspect that he would have had a rather long survival period. The results of treatment in the granulocytic group have not been quite so satisfactory in general as those in the lymphocytic. And yet the majority have been remarkably well and able to carry on their usual activities throughout their illness. An example of this, of the granulocytic well-controlled therapy, is this next slide which shows the course of the blood picture in a man who is a model maker in a brass foundry at which he continued to work throughout this 3.5-year period without periods of illness. The arrows at the bottom indicate when the treatments were given in order to keep the leukocyte count low. As a terminal event he developed severe pain in the head and abdomen, sugar became present in the urine in large amounts. He became comatose and, for the first time during his illness, was hospitalised where he died a few days later from a condition which was diagnosed at post mortem examination as cerebral thrombosis. I feel sure that this had nothing to do with the leukaemic process. Unfortunately, a few of our patients were not available for or did not, for one reason or another, follow up treatment in the prescribed manner and so our figures do not show up so well as they might if we could have controlled them better. The causes of death, as observed in this series, are interesting, particularly in that they indicate that more than half of the patients died from diseases not directly related to leukaemia. May I have the next slide? Of the 105 patients who have died, the cause of death in 69 has been established as other than leukaemia. Post mortem examination confirmed the cause of death in 35 of this group. Perhaps those who died from pneumonia or haemorrhage for example should be included with those who died from a disease directly related to leukaemia. The cause of death for 35 patients is recorded as due to leukaemia. Those with severe haemolytic anaemia, localised infection, progression of the leukaemia due to refusal of therapy and a few in whom no other cause could be determined I included in this group. Pneumonia was considered to be the cause of death in 11 patients as you see at the top. This was the most frequent cause of death. However, if one considers all of the cardiovascular group together, there were 21 which is by far the larger number. It is also of interest to note that of the 10 patients who died of multiple infarcts The other 4 patients died of complications directly resulting from chemotherapy. Death followed the use of TEM, nitrogen mustard, aminopterin and urethane together with intravenous injections of ACTH in 1 patient each. The causes of death are otherwise recorded in the table and so are not here considered as caused by chemotherapy: Again 4 different chemicals were responsible: nitrogen mustard, TEM, mercaptopurine with cortisone and Myleran each in 1 patient. The chemotherapy was not, however, carried out by us. You may take that slide off if you wish, although I would like you to note particularly that 5 of our patients died from tuberculosis, and I’ll mention those a little later on, and several from haemorrhage, perhaps because of their severe anaemia, and 6 from sepsis. A solution of potassium arsenide, Fowler’s solution, was used in a number of instances, particularly during the earlier years, but was discontinued because of its unpleasant side effects. At no time during this period of treatment had he been free from severe anorexia and nausea and malaise so that he had lost 40 pounds during that period of time. He was started on spray treatment and within a few weeks had regained his weight for he had no further nausea or vomiting, and lived 2 more years under spray therapy, 4 years in all. The published results of chemotherapy have not been sufficiently impressive to induce us to abandon spray x-ray therapy in its favour. Because we’ve had little personal experience with the use of chemicals other than Fowler’s solution, it is not our intention to attempt to evaluate the comparative effect of x-rays and chemotherapy. A brief record of the experience of some of our patients who received chemotherapy may be of interest and instructive. These patients received it at some time during their period of illness but not as the main course of treatment. Urethane was discontinued after short periods of trial by 6 patients because of anorexia and nausea and vomiting. It was tolerated but had little clinical effect in 1 patient. TEM was discontinued in 1 patient because of anorexia and nausea and in another after twice causing severe leucopoenia. This second patient died of pulmonary tuberculosis after the last trial of TEM. Aminopterin was used once but stopped because of unfavourable effects. Cortisone was given to 4 patients, 2 of whom also received antibiotics. and the forth of a cerebral vascular accident 3 weeks after starting cortisone. These unfavourable experiences with chemotherapy are not sufficient to condemn this method, particularly in view of the fact that it has been given in a few instances in which the disease may have been in a terminal stage regardless of the type of therapy used. However, in comparison with the absence of toxic effects following the use of x-rays in small dosage by the spray technique and because of the lack of evidence of superiority of chemotherapy over that of spray x-ray and reports thus far available, one may question the advisability of further experiment with the chemicals presently in use. Lawrence has reported on favourable experiences with the use of radioactive phosphorus, P32. And Osgood has compared the effects of P32 with the spray therapy showing no definite advantage of one over the other. Where spray treatment is available, it would seem to be the treatment of choice for the patient with chronic leukaemia. Unfortunately, the research during the past 40 years has not produced a strikingly important development for the treatment of chronic leukaemia. Perhaps the most important development has been the introduction of the spray method of Roentgen irradiation, as used in this series of patients, which has tended to minimise some of the unpleasant side effects of therapy and so allowed the patients to live more comfortably and normally throughout their illness. There may also have been added a few years to the lifespan, and even more may be possible, now that infections may be controlled and the use of the sulphonamides and antibiotics available. The majority of the patients in this series were treated before these substances were generally available. Anaemia has been a frequent and important complication as might be expected. Transfusions have been given when indicated. They have, undoubtedly, added both to the lifespan and to the comfort of the patient. Both iron and injections of either liver extract or vitamin B12 have been used in some patients for control of the anaemia but probably not with strikingly beneficial effects, for we have seen the blood levels improve after spray therapy or x-ray therapy whether or not these substances were given. Experimental work in the future in order to be successful in the management of leukaemia, whether acute or chronic, must be directed toward finding a means of encouraging normal production or maturation of leukocytes rather than their destruction. All of our methods of therapy up to date are designed to destroy cells rather than to increase their production or maturation from a normal point of view. Or one must direct attention toward prevention of the disease by recognition of those factors which may initiate the abnormal growth of cells so that these may be avoided. I have already commented on those irritants that are known. And by controlling exposure to these I am sure that some cases of leukaemia can be prevented. I hope that we can learn more of the mechanism by which these substances do produce irritation and so produce leukaemia and in the near future be able to prevent rather than try to cure the disease which now of course is incurable. Thank you.

William Murphy (1960)

X-Ray Treatment of Chronic Leukemia

William Murphy (1960)

X-Ray Treatment of Chronic Leukemia

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